ataluren for nonsense mutation methylmalonic acidemia

Conditions: Amino Acid Metabolism, Inborn Errors

Summary: methylmalonic acidemia (mma) is a rare genetic disorder caused by mutations in the gene for mitochondrial enzyme methylmalonyl-coa mutase (mcm) or in one of the genes for adenosylcobalamin (adocbl). lack of these proteins causes toxic elevations of methylmalonic acid (mmacid) in blood, urine, and other tissues. a specific type of mutation, called a nonsense (premature stop codon) mutation, is the cause of the disease in approximately 5% to 20% of participants with mutations in the mcm gene, and approximately 20% to \>50% of participants with mutations in one of the adocbl genes. ataluren is an orally delivered, investigational drug that acts to overcome the effects of the premature stop codon, potentially enabling the production of functional mcm/adocbl. this study is a phase 2a trial evaluating the safety and activity of ataluren in participants with mma due to a nonsense mutation. the main purpose of this study is to understand whether ataluren can safely decrease mmacid levels.

in this study, participants with mma due to a nonsense mutation will be administered an investigational drug called ataluren. evaluation procedures to determine if a participant qualifies for the study will be performed within 14 days prior to the start of drug administration. eligible participants who elect to enroll in the study will then participate in 2 drug administration and follow-up periods. within the first period, ataluren will be taken 3 times per day with meals for 28 days at doses of 5 milligrams/kilograms (mg/kg) (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there will then be an interval of approximately 21 days without ataluren. within the second period, ataluren will be taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there will then be an interval of approximately 14 days without ataluren. during the study, ataluren activity, safety, and pharmacokinetics will be evaluated, and mmacid levels in blood and urine will be measured periodically.

Eligibility criteria:
major inclusion criteria: * ability to provide written informed consent (parental/guardian consent if applicable)/assent (if applicable) * age ≥2 years * phenotypic evidence of methylmalonic acidemia (mma) based on the presence of characteristic clinical symptoms or signs and an elevated plasma mmacid level (\>0.27 micromole/liter (umol/l) * presence of a nonsense mutation in at least 1 allele of the mutase (mut), cobalamin a (cbla), or cobalamin b (cblb) gene * glomerular filtration rate ≥30 milliliters (ml)/minutes/1.73 meters squared (m\^2), serum aminotransferase values ≤2.5\*the upper limit of normal, serum bilirubin ≤1.5\*the upper limit of normal, plasma adrenocorticotropic (acth) within normal limits * willingness and ability to comply with scheduled visits, drug administration plan, study restrictions, and study procedures major exclusion criteria: * known hypersensitivity to any of the ingredients or excipients of the study drug * any change in chronic treatment for mma within 2 months prior to start of screening laboratory assessments * episode of metabolic decompensation within 1 month prior to start of screening laboratory assessments * history of organ transplantation * ongoing dialysis for renal dysfunction